Keywords
SGLT2 inhibitor
Finerenone
Combination therapy
Cardiovascular outcomes
Renal outcomes
Type 2 diabetes
Chronic kidney disease
Meta-analysis
Cardiometabolic risk
Abstract
Background
Combination therapy with glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2і), and/or finerenone offers a strategy to reduce the risk of adverse cardiovascular and renal outcomes. This study aimed to quantify the cardiorenal benefits of combination regimens with GLP-1RA, SGLT2і, and/or finerenone versus corresponding monotherapies.
Methods
MEDLINE and Embase were systematically searched, yielding four post hoc analyses of randomized controlled trials (RCTs) and ten observational studies that met prespecified inclusion criteria. Among RCTs, a random-effects meta-regression was performed to assess whether the effect of GLP-1RAs on cardiorenal outcomes differed based on baseline SGLT2і use. Additionally, for observational studies, random-effects meta-analyses were performed to estimate the effect of combination therapy versus monotherapy on the risk of cardiorenal outcomes.
Results
Across RCTs, p for interaction was>0.05 for major adverse cardiac events (MACE) (p=0.730), cardiovascular (CV) mortality (p=0.889), non-fatal myocardial infarction (MI) (p=0.237), non-fatal stroke (p=0.696), all-cause mortality (p=0.682), heart failure (HF) hospitalization (p=0.257), and renal composite outcome (p=0.890), supporting that GLP-1RAs result in a consistent reduction in outcomes irrespective of baseline SGLT2і use. In observational trials, compared to НЗКТГ monotherapy, GLP-1RA and SGLT2і combination therapy significantly reduced MACE (HR 0.59, 95 % CI 0.47–0.75), MI (HR 0.73, 95 % CI 0.61–0.88), stroke (HR 0.72, 95 % CI 0.53–0.97), all-cause mortality (HR 0.57, 95 % CI 0.48–0.67), and HF hospitalization/events (HR 0.71, 95 % CI 0.59–0.86). Compared to GLP-1RA monotherapy, SGLT2і and GLP-1RA combination therapy significantly reduced CV mortality (HR 0.35, 95 % CI 0.15–0.81), MI (HR 0.93, 95 % CI 0.88–0.97), stroke (HR 0.92, 95 % CI 0.88–0.96), all-cause mortality (HR 0.59, 95 % 0.49–0.70), HF hospitalization/events (HR 0.84, 95 % CI 0.81– 0.88), and serious renal events (HR 0.43, 95 % CI 0.23–0.80). Compared to either SGLT2і or finerenone monotherapy, SGLT2і and finerenone combination therapy significantly reduced all-cause mortality and major adverse kidney events.
Conclusion
Combination therapy with GLP-1RA, SGLT2і, or finerenone confers cardiorenal protection beyond monotherapy in T2D, as supported by concordant evidence from RCTs and large real-world cohorts. These findings support broader clinical adoption of dual-agent strategies but also underscore the need for dedicated prospective trials powered to assess hard clinical outcomes with dual-agent strategies.
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Стаття надійшла в редакцію: 15.01.2026/Received: 15.01.2026
Після доопрацювання: 01.02.2026/Revised: 01.02.2026
Прийнято до друку: 16.02.2026/Accepted: 16.02.2026
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